Triethylamine → 5-fluoro-3-{1-[2-(2-methyl-5-nitrophenyl)ethyl]piperidin-4-yl}-1H-indole

HRID 351769Notes

Reaction equation

HRID 351769 reaction equation
[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Br[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH3:29].C(N(CC)CC)C>CN(C)C=O.CC(=O)CC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][C:20]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=2[CH3:29])[CH2:13][CH2:12]1

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 117699295-fluoro-3-(piperidin-4-yl)-1H-indoleHCID 227143952-(2-Bromoethyl)-1-methyl-4-nitrobenzene

Product 1

HCID 227144005-fluoro-3-{1-[2-(2-methyl-5-nitrophenyl)ethyl]piperidin-4-yl}-1H-indoleYield 76.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6569Methyl Ethyl KetoneSolvent

Procedure

A mixture of 5-fluoro-3-(piperidin-4-yl)-1H-indole (2.7 g) in dimethyl formamide (75 mL), 2-(2-bromoethyl)-1-methyl-4-nitrobenzene (3.7 g) in butanone (200 mL) and triethylamine (9.3 mL) was boiled under reflux for 20 h, and the resulting mixture was concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/triethylamine 100:4) to give 5-fluoro-3-{1-[2-(2-methyl-5-nitrophenyl)ethyl]piperidin-4-yl}-1H-indole (3.6 g), which subsequently was dissolved in acetic acid (25 ml) followed by the addition of ethanol (75 mL) and platinum oxide (50 mg). The resulting mixture was shaken under 3 atmosphere hydrogen pressure for 3 h at room temperature. The mixture was reduced in vacuo (50 mL), poured onto an ice/water mixture followed by the addition of aqueous ammonia to basic pH. The aqueous phase was extracted with an ethyl acetate/tetrahydrofuran mixture, and the combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/ethanol/triethylamine 100:4:4) to give 3-{1-[2-(5-amino-2-methylphenyl)ethyl]piperidin-4-yl}-5-fluoro-1H-indole (1.0 g), which subsequently was dissolved in tetrahydrofuran (45 mL) and triethylamine (1.3 mL) at 5° C. followed by the addition of cyclobutancarbonyl chloride (0.3 g) in tetrahydrofuran (15 mL). The resulting mixture was stirred at 5° C. for 1 h, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/ethanol/triethylamine 100:4:4) to give the crude product that was isolated as the oxalate salt from ethyl acetate as a white crystalline compound (0.7 g). Mp 116-125° C. 1H NMR (DMSO-d6): 1.75-1.85 (m, 1H); 1.85-2.05 (m, 3H); 2.05-2.25 (m, 6H); 2.30 (s, 3H); 2.90-3.25 (m, 8H); 3.65 (d, 2H); 6.85-6.95 (m, 1H); 7.10 (d, 1H); 7.25 (s, 1H); 7.30-7.40 (m, 2H); 7.40 (d, 1H); 7.55 (s, 1H); 9.65 (s, 1H); 11.00 (s, 1H). MS m/z: 434 (MH+).

Workup

  1. temperatureunder reflux for 20 h
  2. concentrationthe resulting mixture was concentrated in vacuo
  3. customThe residue was purified by flash chromatography on silicagel (eluent:ethyl acetate/triethylamine 100:4)

Sources & evidence

ORD record
ord-e142b19263ad406e9d62bad2f03af62a
Source dataset
uspto-grants-2004_06
Patent number
US06743809B2

Reaction notes

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